Lower alkyl-4-phenyl-1-[(diloweralkoxy phenyl)-aliphatic] piperidine-4-carboxylates



United States PatentO LOWER ALKYL-4-PHENYL-1-[(DIL'OWERALKOXY PHENYL) ALIPHATIC] PIPERIDINE 4 CAR- BOXYLATES No Drawing. Filed Sept. 12, 1955, Ser. No. 533,892

4 Claims. (Cl. 260-2943) The present invention relates to compositions of matter and their preparation, and is concerned with an improve ment in the substituent attached to'the nitrogen atom or l-position of the piperidine ring in the class of chemical compounds identified as lower alkyl 4-phenyl-1-(substituted)piperidine-4-carboxylates. In particular, the compounds of this invention are those having a (substitutedphenyl)-aliphatic radical as the l-substituent.

Attempts have been made for some time to develop analgesics having high activity. The highly potent morphine has the disadvantagesof causing nausea, vomiting, constipation and respiratory depression, and for these reasons has been supplanted largely by meperidine,ethyl 4- phenyl-l-methylpiperidine-4-carboxylate, especially in obstetrics where depression of respiration is highly undesirable. Because of the relatively high dose required, meperidine has to be injected in hypertonic concentrations, with a consequent risk of irritation at the .site of administration. This limits the choice of concentrations which can be used and restricts undesirably the free choice of optimum dosage. This situation is advantageously modified with the compounds of my invention since they are many times more potent as analgesics than meperidine and thus can be administered in smaller volumes of solution and at high therapeutic levels of effectiveness without making the solution hypertonic. This reduces any tendency to undesirable accompanying irritation, and improves the therapeutic usefulness of the medicament.

US Patent 2,167,351 broadly shows lower alkyl 4- aryl-l-(substituted)piperidine-4-carboxylates where the 1- substituent is a monovalent hydrocarbon "radical. Included among the specific examples'are such compounds having l-methyl and l-benzyl substituents, the latter being of value primarily as intermediates for the former. The l-methyl compounds are now known and'accepted as effective, morphine-like central analgesics and atropinelike smooth muscle neurospasmolytics in the relief 'of severe pain. An outstanding example of these l-methyl compounds is the commercially available meperidine hydrochloride, ethyl 4-phenyl-l-methylpiperidine-4-carboxylate hydrochloride. On the other hand, the intermediate l-benzyl compounds have, been found to have a decidedly lower analgesic activity compared withthe l-methyl compounds. For example, ethyl 4-phenylfl-benzylpiperidine- 4-carboxylate as its hydrochloride has been found to be only approximately one-fourth as effective an analgesic as meperidine hydrochloride when tested by the Bass- Vander Brook modification of the DAmour-Smith method. This decrease in activity in going from ,1-

methyl to l-benzyl would indicate that l-phen'ylalkyl substituents are undesirable, and would'thus' lead investigators away from these compounds, and awayfrom compounds such as those of the instant invention.

I have now prepared lower alkyl 4-ph enyl-1-[(, ubsti- 7 strong inorganic or an organic sulfonicacidg iflhe tuted-phenyl) aliphatic] piperidine- 4 carboxylates and surprisingly found them to be; outstandingly superior as analgesics compared with the corresponding l-benzyl preferably by 'the reactionof alowerjalky1*4 .'ph; j

2,918,454 Patented Apr. 4,.

compounds of US. Patent 2,167,351 and, indeed, more effective than the corresponding 1-methyl compounds, even meperidine itself. For example, my ethyl 4-phenyl- 1-[2-(4 aminophenyl) ethyl] piperidine-4-carboxylate as its hydrochloride salt, when measured as hereinbefore mentioned, is approximately ten times as elfective. an analgesic as meperidine hydrochloride, or thus having an analgesic activity approximately forty times that of the corresponding known l-benzyl compound. In addition to having this high analgesic activity, my compounds have a relativelyilow toxicity for exarnp1 e,, ethyl t-phenyl-l [2 (4 A aminophenyDethyl]-piperidine 4-carboxylate hydrochloride is only about twice as toxic [intravenoustox icity in mice when measured by.a procedure similar to that described by Hoppe et al., J. Pharm, & Exp. .Therap, 95, 502 (1949)] as meperidine hydrochloride, ,so that its therapeutic index compared with meperidine hydrochloride is approximately five. I s l f My compounds in free base form have the formula Call; /0 O 0-(lower alkyl) Ji-Ar where X is a lower divalent aliphatic hydrocarbon radical and Ar is a phenyl radical having at least one substituentl The lower alkyl radical of the above formula pr'e'fer ably has from one to six carbon atoms inclusive, and includes such radicals as methyl, ethyl, n-propyl, isopro pyl, n-butyl, isobutyl, Z-butyl, n-amyl, n-hexyl; andthe like.

The 'substituted-phenyl radical designated-above'as Ar can have preferably from one to three substituents'such as nitro, amino, (lower alkyl)amino, di-(lower alkyl)- 7 amino, (lower alkanoyl)amino, lower alkoxy, lower alkylmercapto, lower alkylsulfonyl, hydroxy, halo, and the like. Furthermore,.these substituentscan be in any- V V of the available positions of the phenyl nucleus, and where more than one substituent, they 'can be the-same I or different and theycan be in any of the .variousposi-V tion combinations relative to each other. The (lower, alkyl)amin0, (lower alkanoyl) amino, loweraalkox'y', lower alkylmercaptoand lower alkylsulfonyl substituents, and the lower alkyl radicals of said di-(lower alkyl) amino. substituent, each have preferably from one toisixcarbon atoms which can be arranged as straightorbranchedchainsl 1- j L The lower divalent aliphatic hydrocarbon radical de'si' nated above as X can have from one to'six carbon atorn andpreferably has from two to four carbon atoms find f HaC afl 5 i and thelikef I The compounds-of this invention can'beaprcpai'eii piperidinel-carboxylate with an equimolaramountiof the appropriate (substituted-phenyl)aliphaticfestergof tion is generally carried out at a temperature bet about 50.f C. and '150 C., preferablylati" lower alkanol solvent. Other methods, such" tli tion ofa lowercalkyl 4 phenylpiperidiiie-4-c with the appropriate aldehyde under catalytic hydrogenation conditions, can be used.

A preferred subgenera of my invention are the compounds havingin free base form the following formula C O (lower alkyl) C C CH where X is an alkylene radical having from two to four carbon atoms inclusive and having its free valence bonds on different carbon atoms, are prepared by the steps of reacting a lower alkyl 4-phenylpiperidine-4-carboxylate with a nitrophenyl-alkylating agent, said agent being preferably a nitrophenylalkyl ester of a strong inorganic acid or an organic sulfonic acid, said ester having the formula where An is an anion of a strong inorganic acid or a sulfonic acid, and reducing the resulting lower alkyl 4- phenyl 1 [(nitrophenyl)alkyl]piperidine 4 carboxylate with a reducing agent effective to reduce nitro groups to amino groups. Illustrative of the nitrophenylalkyl esters used in the first step are 2-(4-nitrophenyl)- ethyl bromide, 3-(3-nitrophenyl)propyl chloride, 2-(2- nitrophenyl) propyl iodide, 4-(4-nitrophenyl) butyl sulfate, 2 (4 nitrophenyl)ethyl methanesulfonate,.3 (3 nitrophenyl)propyl benzenesulfonate, 2 (4 nitrophenyl)- butyl para-toluenesulfonate, and the like. The preferred nitrophenylalkyl esters are the bromides, e.g., 2-(4-nitrophenyl)ethyl bromide. This first step is carried out by heating the lower alkyl 4-phenylpiperidine-4-carboxylate with the appropriate nitrophenylalkyl ester in the presence or absence of a suitable solvent, but preferably in the presence of a solvent such as a lower alkanol. I found the reaction to take place readily in refluxing n-butanol with stirring in the presence of an alkaline agent such as sodium carbonate to neutralizethe hydrogen halide formed by the reaction. The nitrophenylalkyl compound is isolated in free base form or in the form of an acid addition salt. These intermediate nitro compounds are also useful as analgesic agents.

The reduction of the nitrophenyl compounds to the corresponding aminophenyl compounds can be carried out either by chemical methods or by catalytic hydrogenation. Suitable chemical reducing agents are iron and hydrochloric acid, ferrous sulfate and ammonia, tin and hydrochloric acid, sodium hydrosulfite, and. the like. Catalysts suitable when catalytic hyd g ti n is d propyl]piperidine-4-carboxylate is prepared by reacting l 4 include Raney nickel, platinum, palladium or other catalysts generally effective to catalyze hydrogenation of nitro groups to amino groups. In practicing my invention, I preferably used the catalytic hydrogenation procedure using the platinum oxide catalyst. The resulting ammophenylalkyl product is isolated in free base form or in the form of an acid addition salt.

The lower alkyl 4-phenyl-1-[(aminophenyl)-aliphatic]- piperidine-4-carboxylate having the formula CU S COO-(lower alkyl) CH1 CH:

CH: CHI

where X is an unsaturated divalent hydrocarbon radical having from two to four carbon atoms inclusive and having its free valence bonds on different carbon atoms, are prepared following the procedure described above for corresponding l-[(arninophcnyl)alkyl] compounds, i.e., where X is a corresponding saturated divalent hydrocarbon radical, except that the nitro group is selectively reduced using chemical reducing agents such as ferrous sulfate and alkali or hydrazine hydrate and alkali, or by catalytic hydrogenation using Raney nickel as the catalyst, without effecting the double or triple bond of the unsaturated X. For example, ethyl 4-phenyl-l-[3-(4-aminophenyl) 2 propenyl1piperidine 4 carboxylate is formed by heating ethyl 4-pheny1piperidine-4-carboxylate with 3-(4-nitrophenyl)-2-propenyl bromide and treating the resulting ethyl 4-phenyl-1-[3-(4-nitrophenyl)-2-propenyl]piperidine-4-carboxylate with hydrogen under pressure in the presence of Raney nickel as the catalyst to reduce the nitro group to amino. Similarly, ethyl 4- phenyl l 1 [3 (4 aminophenyl) 2 propynylJpiperidine-4-carboxylate is prepared following the above procedure but using 3-(4-nitrophenyl)-2-propynyl bromide in place of 3-(4-nitrophenyl)-2-propenyl bromide.

Other preferred embodiments of my invention are the compounds having the formula where X is a lower divalent aliphatic hydrocarbon radical having from two to four carbon atoms and having its two free valence bonds on different carbon atoms and Ar is (lower alkoxy)phenyl, di-(lower alkoxy)phenyl and (lower alkanoylamino)phenyl. The compounds where Ar is (lower alkoxy)phenyl or di-(lower alkoxy)- phenyl are prepared following the procedure described above for the preparation of the corresponding lower alkyl 4 phenyl 1 [(nitrophenyl) aliphatic] piperidine-4-carboxylates. For example, ethyl 4-phenyl-1-[2- (3,4-diethoxyphenyl)ethyl]piperidine-4-carboxylate is prepared by heating ethyl 4-phenylpiperidine4-carboxylate with 2-( 3,4-diethoxyphenyl)ethyl bromide; and methyl 4 phenyl 1 [3 (4 n butoxyphenyl) 2 propenyl] -piperidine-4-carboxylate is prepared by heating methyl 4 phenylpipcridine 4 carboxylate with 3 (4 nbutoxyphenyl)-2-propenyl bromide. The compounds where Ar is (lower alkanoylamino phenyl are prepared by reacting the corresponding l-[(aminophenyl)-aliphatic] compounds with a lower alkanoylatingwagent such as an alkanoyl halide or alkanoic anhydride. For example, n-propyl 4-phenyl-l-[3-(4-acetylaminophenyl)- n propyl 4 phenyl 1- [3 (4 aminophenyl)propy1]- piperidine 4-carboxylate with -acetyl chloride or acetic anhydride.

My new lower alkyl .4-phenyl-1-[(substituted-phenyl)- aliphatic]piperidine-4-carboxylates are useful in the free base form or in the form of acid addition salts, and these salts are within the purview of the invention. The acids which can be used to prepare acid addition salts are preferably those which produce, when combined with the free base, salts whose anions are relatively innocuous to animal organism in therapeutic doses of the salts, so that '7 the beneficial physiological properties inherent in the free base are not vitiated by'sicle effects ascribable to the anions. In practicing my invention, I foundit convenient to employ the hydrochloride salt. However, other appropriate acid addition salts are those derived from mineral acids such as hydrobromic acid, hydriodic acid, nitric acid, phosphoric acid and sulfuric acid; and organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, quinic acid, methanesulfonic acid, ethanesulfonic acid, and the like, giving the hydrobromide, hydriodide, nitrate, phosphate, sulfate, acetate, citrate, tartrate, lactate, quinate, methanesulfonate and ethanesulfonate salts, respectively.

The following examples will further illustrate the invention without, however, limiting ifithereto.

EXAMPLE 1 A. Lower alkyl 4 phenyl 1 [(nitrophenyl) aliphatic] piperidine-I-carboxylates The preparation of these compounds is illustrated by the following synthesis of ethyl 4-phenyl-1-[2-(4-nitrophenyl)ethyl]piperidine-4-carboxylate: Amixture of 148 g. of 2-(4-nitrophenyl)ethyl bromide, 173 g. of ethyl 4- phenylpiperidine-4-carboxylate hydrochloride, 190 g. of anhydrous sodium carbonate and'l300 ml. of n-butanol was refluxed for twenty-four hours. The precipitated sodium halides were removed from the hot reaction mixture by filtration and the filtrate allowed to stand at room temperature overnight. On stirring this solution, crystals separated. The crystalline material was collected and recrystallized from methanol to yield about 160 g. of product, ethyl 4-phenyl-1-[2-(4-nitrophenyl)- ethyl]piperidine-4-carboxylate, M.P. 112.6-114.2 C. (corn).

Analysis.-Calcd. for C H N O C, 69.09; H, 6.85; 0, 16.73. Found: C, 69.38; H, 7.00; O, 17.05..

When ethyl 4-phenyl-l-[2-(4-nitrophenyl)ethyllpiperidine-4-carboxylate is treated with hydrogen chloride; its

hydrochloride is formed.

The above-described preparation canalso be carried out using ethyl 4-phenylpiperidine-4-carboxylate in free base form and only onehalf as much sodium carbonate. Alternatively, this preparationcan be carried. out. using B. Ethyl 4 phenyl I [2 (2 nitrophenyl) ethyl] piperidine- 4-carboxyl ate I i This compound was prepared following the procedure described above in Example 1A for the synthesis of the corresponding 1-[2-(4-nitrophenyl)ethyl] compound us-' ing 52 g. of 2-(2-nitrophenyl)ethyl bromide, 61 g. of ethyl 4-phenylpiperidine-4-carboxylate hydrochloride, 70 g. of anhydrous sodium carbonate and 450 ml. of n-bu-' tanol. The product, ethyl 4-phenyl-1- [2-(2-nitrophenyl)-' ethylJpiperidine 4 carboxylate, as its hydrochloride, melted at 187.6-19l.4 C. (corn). 1

Analysis.-Calcd. for C H N O .HCl: C, 63.09; H, 6.50; O, 15.28. Found: C, 63.04; H, 6.41; O, 15.10.

C. Ethyl 4 phenyl 1 [4 4 nitrophenyl )butyl]piperidine-4-carboxylate I This compound was prepared following the procedure described in Example 1A using 12.2 g. of 4-(4-nitrophenyl)butyl bromide, 12.7 g. of ethyl 4-phenylpiperidine-4-carboxylate hydrochloride, 15 g. of anhydrous sodium carbonate and 150 ml. of n-butanol. The prod- I uct, ethyl 4-phenyl-l-[4-(4Pnitrophenyl)butyl]piperidine 1 I other esters such as 2-(4-nitrophenyl)ethyl para-toluenesulfonate orchloride in place of 2-(4-nitrophenyl)ethy1 bromide. g Following the above procedure but using the appropriate lower alkyl 4-plienylpiperidine-4-carboxylate in placei of ethyl4-phenylpiperidine-4-carboxylate and using the appropriate nitrophenyl-aliphatic halide in place of 2-(4-nitrophenyl)ethyl bromide, there is obtained the following compounds:

methyl 4-phenyll- [4- (4-nitrophenyl) butyl pip eridine-4- I carboxylate, I ethyl 4 phenyl 1 [3 (4 nitrophenyl) 1.2 propenyl] pipetidinel-carboxylate, ethyl 4 phenyl 1 [3 (4 nitrophenyl) 2 propynyl]piperidine-4-carboxylate, isopropyl 4-phenyl 1- [3-(4-nitrophenyl)propylJpiperidine-4-carboxylate, V n-butyl 4-phenyl-1- [2- (2-nitrophenyl propyl] piperidine- 4-carboxylate,

n hexyl 4-phenyl-1- [2- (4-nitrophenyl) ethyljpip eridine-4 carboxylate, and the like.

4-carboxylate, as its hydrochloride, -melted' at 170.6-

.172.6.C. (corn).

Analysis.Calcd. for c ',H,,N,0.,.Hc1= C,,.64.49;"H,; 6.99;'0,14.32. 4 Found: 0, 64.45; H, 6.77; 0,1411. D. Ethyl 4 phenyl 1 (4 nitrobenzyl hiperidi ne 54L carboxylate This compound was prepared following the procedure v 1 described in Example 1A using 34.4 g. of 4-nitrobenz'yl, chloride, 54.0 g. of ethyl 4-phenylpiperidine-4-carboxylate hydrochloride, 60.0 g. of anhydroussodiurn carbona 4 and 300ml; of n-butanol. The product, ethyl 4-phe 1 1-(4-nitrobenzyl)piperidine 4-carboxylate, in .free 1 form, melted at 83.4 85.2 C. (corn). v

Analysis.-Calcd. for C H N Q i C, 68.46 11,657- 0, 17.38. Founda'C, 68.36; H, 6.66; O, 17.30

When ethyl 4 phenyl 1 (4 '-nitrobenzyDpipendine 4-carboxylate is treated-with hydrogen chloride, i drochloride is, formed. r t

I EXAMPLE-2 7 A. Loweralkyl 4-phe nyl-1'-[(amirpophenyl piperidine-4-carboxylates The preparation ,of these compounds Where the all, phatic portion of the (aminophenyD-aliphafic substituent is saturated is illustrated by the following preparati of; ethyl 4-phenyl-1-[2-(4-aminophenyl)ethyl]piperidin 4' carboxylate: 83 g. of ethyl 4-phenyl-1-[ 2 (4-nitrophen ethyl] piperidine-4-carboxylatewas suspended in1'400 m of absolute ethanol and agitated with hydrogen und .1 initial pressure of 825 lbs per sq. in. (final pressu off 720 lbs. per sq. in.) in the presence of platinum o'xide room temperature. The catalyst was removed by .filtra- 1 tion, and 38 ml. of concentrated hydrochloric acid was added to the filtrate whereupon a white 'precipitateisep" arated.. Three recrystallizations of this "material; once from isopropanol-water, once from .ethanol waterfan' once from acetone-water yieldedabout 45 g of prod f 75, ethyl 4-phenyl-1-[2-(4;aminophenyl)eth pi carboxylate in the form of its dihydrochloride, M.P. softened at 247.4 C. (corn) and then decomposed slowly.

Analysis.-Calcd. for C H N O QHCI: C, 62.12; H, 7.11; Cl, 16.67. Found: C, 62.03; H, 6.91; Cl, 16.48.

Ethyl 4 phenyl 1 [2 (4 aminophenyl)ethyl]- piperidine-4-carboxylate in the form of its free base is obtained by dissolving a sample of the above-described dihydrochloride in water, treating the aqueous solution with sodium hydroxide solution, extracting the liberated bae with benzene, drying the benzene extract over anhydrous sodium sulfate, evaporating the benzene solution slowly to dryness in vacuo, chilling to induce crystallization, and recrystallizing to constant melting point from ethanol-water. The resulting product is ethyl 4-phenyl-1- [2- 4-aminophenyl) ethyl] pip eridine-4-carb oxylate.

Other lower alkyl 4 phenyl-1-(aminophenylalkyDpiperidine-4-carboxylates that are obtained following the foregoing procedure using the appropriate intermediate lower alkyl 4-phenyl-l-(nitrophenylalkyl)piperdine 4 carboxylate are: methyl 4-phenyl-1-[4-(4-aminophenyl)butyl] piperidine-4-carboxylate, isopropyl 4-phenyl 1 [3- (3- aminophenyl)propyl] piperidine-4-carboxylate, n-butyl 4- phenyl-l- [2-(2-aminophenyl)propyl] piperidine-4- carboxylate, and n-hexyl 4-phenyl-1-[2-(4-aminophenyl)-etl1yl] piperidine-4-carboxylate.

Lower alkyl 4-phenyl-1-[(aminophenyl) alkenyl or -alkynyl]piperidine-4-carboxylates are obtained following the foregoing procedure using the appropriate lower alkyl 4- phenyl-1-[(nitrophcnyl)-alkenyl or -alkynyl]piperidine- 4-carboxylate and Raney nickel as the catalystso as to selectively reduce the nitro group to amino without affooting the double or triple bond of the alkenyl or alkynl portion of the l-s ubstituent. Illustrations of these unsaturated compounds that can be prepared in this manner are: ethyl 4-phenyl-1-[3-(4-aminophenyl)-2- propenyl]piperidine-4-carboxylate and ethyl 4-phenyl-l- [3-(4-aminophenyl -2-propynyl] piperidine-4-carboxylate.

These compounds can be isolated in their free base form or in the form of their dihydrochloride salts.

Pharmacological evaluation of ethyl 4-phenyl-1-[2-(4- aminophenyl) ethyl] piperidine-4-carboxylate dihydrochloride in aqueous solution administered subcutaneously by the Rat Thermal Stimulus Method of Bass and Vander Brook, ibid., has shown that this compound is approximately ten times as active an analgesic as ethyl 4-phenyl- 1-methylpiperidine-4-carooxylate hydrochloride. The compound was found to have an acute toxicity in mice of 17.8:09 mg; per kg. when administered intravenously in aqueous solution.

B. Ethyl 4-plzenyl-1-[Z-(Zmminophnyl) ethyl] piperidine- 4-carb0xylate C. Ethyl 4-phenyl-1- [4- (4-amin0phenyl) butyl] piperidine- 4-carb0xylate This compound is prepared following the procedure described above in Example 2A using ethyl 4-phenyl-1- [4-(4-nitrophenyl)butyl]piperidine-4-carboxylate in place of the corresponding l-[2-(4-nitrophenyl)ethyl]compound. The product can be obtained as its free base or in the form of its dihydrochloride salt.

D. Ethyl 4-phenyl-1-(4-aminobenzyl) piperidine-4-carboxylate This compound is prepared following the procedure described above in Example 2A using ethyl 4-phenyl-l- (4-nitrobenzyl)piperidine-4-carboxylate in place of the corresponding 1;;[2-(4-nit'ropheny1)ethyl]compound. The

product can be obtained in the form of its free base or as its dihydrochloride salt.

EXAMPLE 3 A. Lower alkyl 4-pIzenyl-1-[(alkoxyphenyl)-aliphatic] piperidine-4-carb0xylates The preparation of these compounds is illustrated by the following synthesis of ethyl 4-phenyl-1-[2-(3,4-dimethoxyphenyl)ethyl]piperidine-4-carboxylate: A mixture of 13.5 g. of 2 -(3,4-dirnethoxyphenyl)ethyl bromide, 14.2 g. of ethyl 4-phenylpiperidine-4-carboxylate hydrochloride, 15 g. of anhydrous sodium carbonate and 100 ml. of n-butanol was refluxed for twenty-four hours. The reaction mixture was filtered to remove the precipitated sodium chloride and sodium bromide, and the filtrate was treated with solid carbon dioxide to remove any of the unreacted ethyl 4-phenylpiperidine-4-carboxylate. After filtering again, the filtrate was treated with hydrogen chloride and the resulting white solid precipitate was cob lected and recrystallized several times from Water to yield the product, ethyl 4-phenyl-1-[2-(3,4-dimethoxyphenyl)- ethyl]piperidinel-carboxylate as its hydrochloride, M1. 1804-1852 C. (corn). 7 Analysis.Calcd. for C H NO .HCl: C, 66.42; H, 7.43; O, 14.71. Found: C, 66.36; H, 7.49; O, 15.05.

Ethyl 4-phenyl-1- [2- 3 ,4-dimethoxyphenyl ethyl] piperidine-4-carboxylate in free base form is obtained by treating an aqueous solution of its hydrochloride salt with aqueous sodium hydroxide solution, extracting the liberated base with benzene, drying the benzene extract with anhydrous calcium sulfate and removing the benzene by distillation in vacuo.

The above-described preparation can also be carried out using ethyl 4-p11enylpiperidine-4-carboxylate in free base form and only one-half as much sodium carbonate. Alternatively, this preparation can be carried out using other esters such as 2-(3,4-dimethoxyphenyl)ethyl paratolucnesulfonate or chloride in place of the bromide.

Following the above procedure but using the appropriate lower .alkyl 4-phenylpiperidine-4-carboxylate and the appropriate (alkoxyphenyl)-aliphatic halide, there is obtained the following compounds: methyl 4-phenyl-1- [4- 4-ethoxyphenyl) butyl] piperidine-4-carboxylate, ethyl 4 phenyl-l-[3-(3,4-dimethoxyphenyl)-2-propenyl]piperidine-4-carboxylate, ethyl 4-phenyl-1-[3-(3,4,5-trimethoxyphenyl) 2 propynyl]piperidine 4-carboxylate, isopropyl 4 phenyl l-[3-(4-n-butoxyphenyl)propyl]piperidine 4 carboxylate, n-butyl 4-phenyl-1-[2-(3-ethoxyphenyl)propyl]piperidine-4-carboxylate, n-hexyl 4-phenyl 1- [2-(3,4-dimethoxyphenyl)ethyl]-piperidine-4-carboxylate, and the like.

Pharmacological evaluation of ethyl 4-phenyl-l-[2- (3 ,4-dimethoxyphenyl) ethyl] piperidine-4carboxylate hydrochloride in aqueous. solution administered subcutaneously or intraperitoneally by the Rat Thermal Stimulus Method of Bass and Vander Brook, ibid., has shown that this compound is approximately six times as active an analgesicas ethyl 4-phenyl-1-methylpiperidine-4-carboxylate hydrochloride. Ethyl 4-phenyl-1-[2-(3,4-dimethoxyphenyl) ethylJpiperidine 4 carboxylate hydrochloride was found to have an acute toxicity in mice of- 18:2 mg. per kg. when administered intravenously in aqueous solution.

B. Ethyl 4-phenyl-I-[Z-(S-metlzoxyphenyl) ethyl]- piperidine-4-carb0xylate 'f for CaHzgNOEyHCli C,T H, 7.49; (31.8.78. Found: C, 68.70; H, 7.74; Cl, 8.891 Ethyl 4 phenyl 1-[2-(3-methoxyphenyl)ethylJpiperidine-4-carboxylate in the form of its free base is obtained by treating an aqueous solution of its hydrochloride salt with aqueous sodium hydroxide solution, extracting the liberated base with benzene, drying the benzene extract and removing the benzene by distillation in vacuo.

Pharmacological evaluation of ethyl 4-pheny1-1-[2-(3- methoxyphenyl)ethylJpiperidine 4 carboxylate hydrochloride in aqueous solution administered intraperitoneally by the above-mentioned method of Bass and Vander Brook has shown that this compound is approximately three times as active an analgesic as ethyl 4-phenyl-lmethylpiperidine-4-carboxylate hydrochloride.

C. Ethyl 4-phenyl-I-[2-(4-meth0xyphenyl)ethyl1piperidine-4-carboxylate free base form, M.P. 76.878.2 C. (corn) when crystal- 7 lized several times from ethanol. Analysis.Calcd. for C H NO ,C,-75.l9; H; 7.95; 0; 13.06. Fou'ndzC, 75.23;H, 7.74; o,13.00

Ethyl 4'- phenyl 1-[2- (4 methoxyphenyl)ethyl]piperidine-4-carboxylate in the form of its hydrochloride is ob- 'tained byjtreating an ethanol solution of thisfree base with hydrogen chloride and removing the precipitated bydrochloride by filtration. i I a Pharmacological evaluation of ethyl 4-phenyl-1-[2-(4- methoxyphenyl)ethyl]piperidine-4-carboxylate in aqueous solution asjts hydrochloride administered intraperitoneally by the above-mentioned method .of Bass and Vander Brook, has. shown that this compound :is approximately three and one-half times as ,activean. analgesic as ethyl 4-phenyl-1-methylpiperidine-4-carboxylate hydrochloride.

The preparation of these compounds is illustrated by 510 V phen'yl-'1-[3 (3-n-hexanoylaminophenyl) J propyupip'efla dine-4-carboxylate, n-butyl 4-phenyl-1 [2-(2-n propanoyl aminophenyl)propyl]piperdine-4-carboxylate, n-hexyl 4 phenyl-l-[Z (4 acetylamin'o'phenyl)ethylJpiperidihe 4 carboxylate, I ethyl 4-phenyl-1-[3-(4-acetylaminophenyl)- 2-propenylJpiperidine-4-carboxylate, ethyl 4-phenyl-l-[3- (4-acetylaminophenyl)-2-propynyl]piperidine-4-carboxylate, eth'yl 4 phenyl-l-[Z (2 acetylaminophenyl) ethyl] piperidine 4 carboxylate, ethyl 4-phenyl-l-[4-(4eacetylaminophenyl)butylJpiperidine 4 carboxylate, ethyl 4- phenyl 1 (4-acetylamiuobenzyl)piperidine 4 carboxylate, and the like.

Pharmacological evaluation of ethyl 4-phenyl-l-[2-(4- acetylaminophenyl)ethyl]piperidine-4-carboxylate hydrochloride in aqueous solution administered intraperitoneally by the Rat Thermal Stimulus Method of Bass and Vander Brook, ibid., has shown that this compound is approximately six and one-half times as active an analgesic as ethyl 4-phenyl-l-methylpiperidine-4-carboxylate hydrochloride. g t EXAMPLE 5 Lower alkyl 4-phenyl-1-[(hydroxyphenyl)aliphatic] piperidine-4-carb0rylates in Example 1A using 4g. of 2-(3-hydroxyphenyl)ethyl bromide, 5.38 g. of ethyl 4-phenylpiperidine-4-carboxylate hydrochloride, 6.3 g. of anhydrous sodium carbonate and 75 ml. of n-butanol. The product, ethyl 4-phenyl-l-[2- 3-hydroxyphenyl) ethyl] piperidine 4 carboxylate, M.P.

' 127.7l38.2 C. (corn).

the following synthesis of ethyl 4-phenyl-l-[2-(4-acetylaminophenyl)ethyl]piperidine-4-carboxylate: To a solution of 8.1 g. of ethyl 4-phenyl-1-[2-(4-aminophenyl)- ethyl]piperidine-4-carboxylate in a mixture of cc. of water and 50 cc. of acetic acid was added 2.54 g. of acetic anhydride, and the resulting solution was warmed on a steam bath for about thirty minutes. Two ml. of concentrated hydrochloric acid was added and the white precipitate that formed was collected, recrystallized from water, and washed with acetone. There was thus obtained about 4.7 g. of white needles, ethyl 4-phenyl-l-[2-(4 acetylaminophenyl)ethyl]piperidine-4-carboxylate hydrochloride, M.P. 266.0-268.0 C. (corn) (with decomposition) when dried at 85 C. overnight.

Analysis.--Ca1cd. for C 4H N O .HCl: C, 66.88; H, 7.25; Cl, 8.23. Found: C, 66.80;H. 7.06; CI, 8.33.

Ethyl 4-phenyl-1- [2-(4-acetylaminophenyl)ethyl]piperidine-4-carboxylate in free base form is prepared by treating an aqueous solution of its hydrochloride with aqueous sodium hydroxide solution, extracting the liberated base with benzene, drying the benzene extract with anhydrous calcium sulfate and removing the benzene by distilling in vacuo.

Following the above procedure but using the appropri 70 ate lower alkyl 4-phenyl-1-[(arninophenylkaliphaticj piperidine-4-carboxylate and the appropriate alkanoyl anhydride or alkanoyl halide, there is obtained the following compounds: methyl 4-phenyl-l-[4-(4-n-butanoylaminophenyl)butyl]piperidine-4-carboxylate,

isopropyl4- iodophenyl)butyl]piperidine-4-carboxylate,f I

Analysis.Calcd. for C H 7NO C, 74.75; H, 7.70; O, 13.56. Found: C, 74.81; H, 7.57; O, 13.00. a

When ethyl 4-phenyl-l-[2-(3-hydroxyphenyl)ethyl]piperidine-4-carboxylate is treated with hydrogen chloride, its hydrochloride is'formed. 1 Following the above procedure but using the appropri ate reactants, other lower alkyl 4-phenyl-1-[(hydroxy-' phenyl)-aliphatic]piperidine-4 carboxylates are obtained, as follows:. ethyl 4-phenyl-1-[3-(4-hydroxyphenyl)pro- I pyl]piperidine-4-carboxylate, ethyl 4-phenyl-1-[3-(4-hydroxyphenyl)-2-propenyl]piperidiue-4-carboxylate, ethyl. 4-phenyl-l-[3-( 3,4 dihydroxyphenyl )-2-propynyl]piperidine-4-carboxylate, methyl 4-phenyl-1-[4-(2-hydroxyphenyl)butyl]piperidine-4-carboxylate, isobutyl 4-phenyl-l- [2- 3-hydroxyphenyl)ethyl]piperidine-4-carboxylate, and-the 1; like. 5

EXAMPLE 6 Lower alkyl 4-phenyl-1-[(halophenyl)-aliphaiic]piperi- Q dine-4-carboxylates The preparation of these compounds is illustrated by g the following synthesis of ethyl 4-phenyl-l-(2-chloro benzyl)piperidine-4-carboxylate: This compound was. prepared following the procedure described above for 'Example 1A using 8.05 g. of 2-chlorobenzyl chloride, n

13.5 g. of ethyl 4-phenylpiperidine-4-carboxylate hydro chloride, 15 g. of anhydrous sodium carbonate and p. j ml. of n-butanol. There was thus obtained about 8.2 g. 'f of ethyl 4-phenyl-l-(2-chlorobenzyl)piperidine 4'- carboxylate, M.P. 68.7-70.9 C. (corn). f Analysis.-Calcd. for C H CINO C, 70.47; H, 6.76; Cl, 9.90. Found: C, 70.64; H, 7.44; Cl, 9.73. f f Following the above procedure but using the appropriate reactants, other lower alkyl 4-phenyl-l-[(halophenylfi' aliphatic]piperidine-4-carboxylates are obtained as, fol lows: ethyl 4-phenyl-1-[2-(4-chlorophenyl)ethyl]piper1 dine-4-carboxylate, ethyl 4-phenyl-1-[3-(2,4-dichlor phenyl)propyl]piperidine-4-carboxylate, ethyl 4-phenyl- 1-[3-(3,4-dibromophenyl) 2 propenyl]piperidine-4-carg boxylate, ethyl 4-phenyl-l-[3-(3 chlorophenyl) 2-pro pynyl] piperidine-4-carboxylate, methyl: 4 phenyl-1g[ 4-,(

EXAMPLE 7 Lower alkyl 4-phenyl-I-[(substituted-phenyl)-aliphatic] piperidine 4-carb0xylates Other lower alkyl 4-phenyl-1-[(substituted-phenyD- aliphatic]piperidine-4-carboxylates that can be prepared following the procedure described in Example 1A using the appropriate reactants'are: ethyl 4-phenyl-l-[2-(4-nbutylaminophenyl) ethyl]piperidine-4-carboxylate, ethyl 4-phenyl-l-[3-(4-n-butylaminphenyl) 2 propenyl] piperidine-4-carboxylate, methyl 4-phenyl-1-[3-(4-dimethylaminophenyl) propyl]piperidine-l-carboxylate, ethyl 4- phenyl-l-[2-(4-n-butylmercaptophenyl) ethyl] piperidine 4-carboxylate, ethyl 4-phenyl-l-[2-(4-n-butylsulfonylphenyl)ethyl]piperidine-4 carboxylate, n-propyl 4-pheny1- 1-[3-(2-chloro-4-ethoxyphenyl)propyl]piperidine 4 carboxylate, and the like. These compounds can be isolated in free base form or in the form. of theirhydrochloride salts.

My lower alkyl 4-phenyl-l-[(substituted-phenyl)-a1iphatic]piperidine-4-carboxylates can be formulated in liquid preparations, e.g., aqueous or aqueous-ethanol menstruum, or in solid form, e.g., tablet or powder. The tablet formulation can be prepared using conventional excipients; and the powder can be compounded in capsule form. These preparations can be administered orally, or, in the case .of the aqueous preparations, intramuscularly or intravenously.

I claim: a

1. A composition of matterselected from the group consisting of a compound having the formula phenyl 12 whereX' is, a lower divalent aliphatic hydrocarbon radical having from two to four carbon atoms and having its two free valence bonds on different carbon atoms and Ar is di-lower alkoxy) phenyl; and its non-toxic acid addition salts.

'2. A lower alkyl 4-phenyl-l-[di-lower alkoxy)pheny1- -alkyl]piperidine-4-carboxylate having the formula phenyl C O O -(lower nlkyl) e t CI\I1 /CH2 N I X (lower alkoxyh where X is an alkylene radical having from two to four carbon atoms inclusive and having its free valence bonds on different carbon atoms.

3. Ethyl .4 phenyl-l-[2-(3,4-dimethoxyphenyl)ethyl] piperidineA-carboxylate.

4. Ethyl 4 phenyl-l-[2-(3,4-dimethoxyphenyl)ethyl] piperidine-4-carboxylate hydrochloride.

References Cited in the file of this patent UNITED. STATES PATENTS 2,167,351 Eisleb July 25, 1939 2,486,795 Kaegi Nov. 1, 1949 2,546,159 Kaegi et a1. Mar. 27, 1951 2,571,515 Archer Oct. 16, 1951 2,794,024 "Ehrhart May 28, 1957 2,824,875 Elpern Feb. 25, 1958 2,841,610 Lott July 1, 1958 2,846,437 Elpern July 5, 1958 2,850,500 Elpern Sept. 2, 1958 OTHER REFERENCES 

1. A COMPOSITION OF MATTER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND HAVING THE FORMULA 